EP0643063B1 - Verfahren zur Herstellung von höheren Kuprat-Komplexen - Google Patents

Verfahren zur Herstellung von höheren Kuprat-Komplexen Download PDF

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Publication number
EP0643063B1
EP0643063B1 EP94116373A EP94116373A EP0643063B1 EP 0643063 B1 EP0643063 B1 EP 0643063B1 EP 94116373 A EP94116373 A EP 94116373A EP 94116373 A EP94116373 A EP 94116373A EP 0643063 B1 EP0643063 B1 EP 0643063B1
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EP
European Patent Office
Prior art keywords
reaction
higher order
complex
produce
preparing
Prior art date
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Expired - Lifetime
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EP94116373A
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English (en)
French (fr)
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EP0643063A2 (de
EP0643063A3 (de
Inventor
Kevin Anthony Babiak
James Richard Behling
John Henry Dygos
John Sau-Hoi Ng
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GD Searle LLC
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GD Searle LLC
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F1/00—Compounds containing elements of Groups 1 or 11 of the Periodic Table
    • C07F1/08—Copper compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention herein is directed to a process for preparing higher order cuprate complexes of the general formula from alkenyl zirconium compounds as reactive intermediates in organic synthesis.
  • the higher order cuprate complexes are derived from the reaction of a cuprate complex with an alkenyl zirconium compound.
  • the higher order cuprate complexes are useful for preparing omega side chains of prostaglandin analogs and more specifically, 16-hydroxy prostaglandin analog side chains.
  • zirconium compounds to prepare prostaglandins is shown in published European catent application 153,689 which describes the preparation of prostaglandin intermediates.
  • the application describes a zirconium compound of the formula wherein X is a halogen and P 1 represents a hydrolyzable protecting group.
  • the zirconium compound is reacted with a compound having the formula wherein CO 2 P 2 represents a hydrolyzable ester group, in an anhydrous, inert organic solvent which contains a salt or a complex of a transition metal as a catalyst.
  • the reaction mixture is treated with a protonating agent to produce a prostaglandin analog compound of the formula
  • the reference describes the use of the zirconium compounds to add an unsaturated omega side chain on a cyclopentenone to form a prostaglandin analog.
  • the reference discloses that the reaction occurs in the presence of a salt or a complex of a transition metal catalyst which includes salts or complexes of nickel, cobalt, iron, manganese and palladium.
  • the reference's preferred complex is a complex or salt of nickel (I) which is produced in situ in the reaction by using a nickel (II) salt (or complex) and a reducing agent.
  • WO-A 9115493 (published after the present priority date but claiming an earlier priority) is related to higher order cuprate complexes by transmetalation from a corresponding zirconate intermediate by reaction with R 2 Cu(A)Li 2 wherein A is CN or SCN.
  • C.A. 114, 61742 to Kalish, Vincent, J., published after the present priority date is related to a method for preparing prostaglandin analogs by hydrozirconation-iodination of a terminal acetylene followed by lithiumiodide exchane and dilithiocyanocuprate- mediated conjugate addition to an appropriate cyclopentenone.
  • the invention herein is directed to a process for preparing a higher order cuprate complex.
  • the process is performed by reacting an alkyne of the formula H ⁇ C ⁇ C ⁇ R 1 with zirconocene chloride hydride, Cp 2 Zr(H)Cl, to produce an E-alkenyl zirconium intermediate of the formula wherein R 1 contains 1 to 20 carbon atoms which can have vinyl unsaturation.
  • R 1 can contain cycloalkyl or cycloalkenyl moieties where the cycloalkyl contains 3 to 6 carbon atoms.
  • R 1 can be substituted with hydroxy, tri-lower-alkylsiloxy, tetrahydropyranyloxy, tetrahydrofuranyloxy, halo or phenoxy.
  • the E-alkenyl zirconium intermediate is reacted with an alkyllithium and a copper-containing reagent selected from: R 2 Cu(CN)Li or the mixture CuCN and R 2 Li to produce a higher order cuprate complex intermediate of the formula wherein R 2 can be alkyl, alkenyl, alkynyl, aryl or heteroaromatic such as 2-thienyl.
  • the invention herein is directed to a process for preparing a higher order cuprate complex.
  • the process herein is advantageous in that the process can be performed in a single reaction vessel to completion in forming the higher order cuprate complex.
  • the invention herein is directed to a process for preparing a higher order cuprate complex comprising the steps of:
  • cuprate complex can be used in further reaction sequences as is known for cuprate reagents for example to make prostaglandin derivatives
  • the process is performed by reacting an alkyne and a zirconocene chloride hydride, Cp 2 Zr(H)Cl, to produce an E-alkenyl zirconium intermediate.
  • Cp represents a cyclopentadienyl anion group.
  • the E-alkenyl zirconium intermediate need not be isolated but can be reacted with an alkyllithium and a copper-containing reagent which can be: the complex R 2 Cu(CN)Li or the reagent mixture CuCN and R 2 Li to produce a higher order cuprate complex intermediate of the formula wherein R 1 contains 1 to 20 carbon atoms which can have vinyl unsaturation.
  • R 1 can contain cycloalkyl or cycloalkenyl moieties where the cycloalkyl contains 3 to 6 carbon atoms.
  • R 1 can be substituted with hydroxy, tri-lower-alkylsiloxy, tetrahydropyranyloxy, tetrahydrofuranyloxy, halo or phenoxy; and wherein R 2 can be alkyl, alkenyl, alkynyl, aryl or heteroaromatic such as 2-thienyl.
  • the higher order cuprate complex intermediate need not be isolated but can be reacted with an appropriate cyclopentenone to produce a prostaglandin derivative
  • reaction Schemes I-II The two reaction schemes illustrate the process herein and the variations in the process.
  • Each of the reaction sequences shown in the reaction schemes can be performed in a single vessel which provides a particularly unique benefit for using the process herein as the performance of the process in a single reaction vessel ("one-pot" reaction) eliminates steps of separating and isolating intermediates and the need for having additional reaction vessels.
  • a wedge shaped bond ( ⁇ ) represents a substituent which has the ⁇ orientation (above the plane of the molecule) and a broken line ( ) represents a substituent that is in the ⁇ orientation (below the plane of the molecule) and a wavy line ( ) represents a substituent which is either in the ⁇ or ⁇ orientation or is a mixture of these isomers.
  • a terminal alkyne is reacted with Cp 2 Zr(H)Cl in a suitable solvent such as tetrahydrofuran (THF) to produce a zirconium intermediate of the indicated formula.
  • the zirconium intermediate is reacted sequentially with two equivalents of an alkyllithium such as n-butyllithium (n-BuLi) or methyllithium (CH 3 Li), copper cyanide (CuCN), an alkyllithium such as methyllithium (CH 3 Li) and an appropriate enone which results in the prostaglandin derivative which is represented in this Scheme I as having TMS and TES (trimethylsilyl and triethylsilyl) protective groups for the hydroxyl moieties on the prostaglandin derivative.
  • the reaction is conducted in a single reaction vessel with the reactants being added in the order indicated.
  • the reaction is performed at a reduced temperature preferably in the range of -50°C to -78°C.
  • reaction sequence shown in Scheme II illustrates another method for preparing prostaglandin derivatives using the invention herein.
  • a terminal alkyne is reacted with zirconocene chloride hydride to yield a zirconium intermediate which is reacted with two equivalents of alkyllithium followed by a lower order cuprate complex, R 2 Cu(CN)Li, and a suitable enone to provide the prostaglandin derivative.
  • the reaction sequence is performed in a temperature range from about -50°C to about -78°C.
  • any conventional inert organic solvent or solvent mixture can be used.
  • Aromatic hydrocarbons such as benzene and toluene and ether solvents such as tetrahydrofuran are especially preferred.
  • Temperatures in the range of -50° to -78°C are preferred for performing the reaction with a temperature range from -50° to -60°C being especially preferred.
  • This example illustrates a one-pot preparation of a higher order cuprate complex using the method herein and in particular following the reaction sequence shown in reaction Scheme I.
  • a dry, round bottom flask was charged with 776 mg (3.00 mmol) of zirconocene chloride hydride and 4 ml of dry THF under nitrogen.
  • a solution of 604 mg (2.85 mmol) of 4-methyl-4-trimethylsilyloxy-1-octyne in 6 ml of THF was added by cannula.
  • the mixture was stirred at room temperature for approximately 30 minutes and cooled to -50°C.
  • the mixture was treated with 3.56 ml of n-butyllithium (1.6M in hexane, 5.7 mmol) for ten minutes.
  • Example 1 The procedure of Example 1 was repeated in very essential detail with the exception that the indicated alkynes shown in the following Table 1 were used.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Catalysts (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Claims (3)

  1. Ein Verfahren zur Herstellung eines Cuprat-Komplexes höherer Ordnung, umfassend die Stufen von:
    (a) in reaktiven Kontakt bringen in einem einzigen Raktionsgefäß von einsm Äquivalent eines Alkins und einer ausreichenden Menge an Zirkonocenchloridhydrid, um ein E-alkenylzirkonium-Zwischenprodukt zu produzieren, und
    (b) Zugabe zum Reaktionsgefäß (i) von zwei Äquivalenten eines Alkyllithiums, gefolgt durch ein Äquivalent R2Cu(CN)Li oder (ii) zwei Äquivalenten eines Alkyllithiums, gefolgt durch ein Äquivalent CuCN und einem Äquivalent R2Li, zur Herstellung eines Cuprat-Komplex-Zwischenproduktes höherer Ordnung, worin R2 eine Alkyl-, Alkinyl-, Aryl- oder heteroaromatische Gruppe sein kann.
  2. Ein Verfahren gemäß Anspruch 1, worin die Reaktion in einem Temperaturbereich von -50 bis -78°C erfolgt.
  3. Ein Verfahren nach Anspruch 1 oder 2, worin das Alkyllithium Methyllithium ist.
EP94116373A 1990-04-17 1991-04-15 Verfahren zur Herstellung von höheren Kuprat-Komplexen Expired - Lifetime EP0643063B1 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US07/510,349 US5055604A (en) 1990-04-17 1990-04-17 Process for preparing prostaglandin analogs using organozirconium compounds
US510349 1990-04-17
EP91105951A EP0452843B1 (de) 1990-04-17 1991-04-15 Verfahren zur Herstellung von Prostaglandin-Analogen mit Hilfe von Organozirkoniumderivaten

Related Parent Applications (2)

Application Number Title Priority Date Filing Date
EP91105951.7 Division 1991-04-15
EP91105951A Division EP0452843B1 (de) 1990-04-17 1991-04-15 Verfahren zur Herstellung von Prostaglandin-Analogen mit Hilfe von Organozirkoniumderivaten

Publications (3)

Publication Number Publication Date
EP0643063A2 EP0643063A2 (de) 1995-03-15
EP0643063A3 EP0643063A3 (de) 1995-10-11
EP0643063B1 true EP0643063B1 (de) 2000-01-26

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EP94116373A Expired - Lifetime EP0643063B1 (de) 1990-04-17 1991-04-15 Verfahren zur Herstellung von höheren Kuprat-Komplexen
EP91105951A Expired - Lifetime EP0452843B1 (de) 1990-04-17 1991-04-15 Verfahren zur Herstellung von Prostaglandin-Analogen mit Hilfe von Organozirkoniumderivaten

Family Applications After (1)

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EP91105951A Expired - Lifetime EP0452843B1 (de) 1990-04-17 1991-04-15 Verfahren zur Herstellung von Prostaglandin-Analogen mit Hilfe von Organozirkoniumderivaten

Country Status (12)

Country Link
US (1) US5055604A (de)
EP (2) EP0643063B1 (de)
JP (1) JPH04224555A (de)
KR (2) KR100208496B1 (de)
AT (2) ATE189222T1 (de)
CA (1) CA2040468C (de)
DE (2) DE69110343T2 (de)
DK (2) DK0643063T3 (de)
ES (2) ES2073060T3 (de)
GR (1) GR3033236T3 (de)
IE (1) IE911273A1 (de)
PT (1) PT97368A (de)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5618959A (en) * 1995-03-10 1997-04-08 Vivus Incorporated Process for preparing prostaglandin E1, E2 and analogs thereof using furylcopper reagents
US6030959A (en) * 1997-04-04 2000-02-29 Monsanto Company Gastro-specific prodrugs
US6413945B1 (en) * 1997-04-04 2002-07-02 Pharmacia Corporation Gastro-specific prodrugs
KR20030002365A (ko) * 2001-06-29 2003-01-09 주식회사 하이닉스반도체 반도체 소자의 포토 레지스트 중합체용 단량체 및 이의제조 방법
KR101045935B1 (ko) 2009-03-11 2011-07-01 연성정밀화학(주) 프로스타글란딘 유도체의 제조방법
HU231185B1 (hu) 2017-07-11 2021-07-28 CHINOIN Gyógyszer és Vegyészeti Termékek Gyára Zrt. Eljárás Misoprostol előállítására és tisztítására

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US3950406A (en) * 1972-07-24 1976-04-13 American Cyanamid Company Hydroxylated 15-deoxy derivatives of 9-hydroxy-13-trans-prostenoic acid
US3962353A (en) * 1972-09-29 1976-06-08 Wisconsin Alumni Research Foundation 3-Substituted iodo alkenyl compounds and methods for preparing same
US3962351A (en) * 1972-09-29 1976-06-08 Wisconsin Alumni Research Foundation 3-Substituted iodo alkenyl compounds and methods for preparing same
US3962352A (en) * 1972-09-29 1976-06-08 Wisconsin Alumni Research Foundation 3-Substituted iodo alkenyl compounds and methods for preparing same
US3932479A (en) * 1973-04-27 1976-01-13 American Cyanamid Company Lithium 3-triphenylmethoxy-1-trans-alkenyl-dialkyl alanates
US4007210A (en) * 1973-04-27 1977-02-08 American Cyanamid Company Novel 3-triphenylmethoxy-1-alkynes, 3-triphenylmethoxy-1-trans-alkenyl-dialkyl-alanes, and lithium 3-triphenyl-methoxy-1-trans-alkenyl-dialkyl-alanates
US3965143A (en) * 1974-03-26 1976-06-22 G. D. Searle & Co. 16-Oxygenated prostanoic acid derivatives
US4983753A (en) * 1981-05-21 1991-01-08 Floyd Jr Middleton B Precursors and synthesis of di-(methyl)-16,16-(dimethyl)-11-alpha,15-alpha beta-dihydroxy-9-oxo-2,13-trans,trans-prostadienoates
US4415501A (en) * 1981-12-16 1983-11-15 American Cyanamid Company Alkenylzirconium reagents useful for prostaglandin analog synthesis
US4822909A (en) * 1983-06-10 1989-04-18 Asashi Glass Company Ltd. 7-fluoroprostaglandins and process for their production
DK40485A (da) * 1984-03-02 1985-09-03 Hoffmann La Roche Prostaglandin-mellemprodukter
DE3571319D1 (en) * 1984-10-08 1989-08-10 Teijin Ltd Process for producing 2,3-disubstituted -4-substituted cyclopentanones, enantiomorphs, or mixtures thereof
US4873360A (en) * 1986-07-10 1989-10-10 Board Of Governors Of Wayne State University Process for the preparation of cyclopentanoids and novel intermediates produced thereby
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US4777275A (en) * 1987-06-09 1988-10-11 G. D. Searle & Co. Process of preparing higher order cuprate complexes
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US5072010A (en) * 1990-04-04 1991-12-10 University Of California Transmetalations from zirconium to copper intermediates

Also Published As

Publication number Publication date
ES2073060T3 (es) 1995-08-01
EP0452843A3 (en) 1992-07-29
DE69131944T2 (de) 2000-06-15
ATE123768T1 (de) 1995-06-15
CA2040468C (en) 2004-10-26
DE69110343D1 (de) 1995-07-20
DK0643063T3 (da) 2000-04-25
DK0452843T3 (da) 1995-08-14
KR910018351A (ko) 1991-11-30
EP0452843B1 (de) 1995-06-14
ES2143517T3 (es) 2000-05-16
EP0452843A2 (de) 1991-10-23
EP0643063A2 (de) 1995-03-15
DE69131944D1 (de) 2000-03-02
ATE189222T1 (de) 2000-02-15
JPH04224555A (ja) 1992-08-13
KR100208496B1 (ko) 1999-07-15
DE69110343T2 (de) 1995-12-21
PT97368A (pt) 1992-01-31
IE911273A1 (en) 1991-10-23
US5055604A (en) 1991-10-08
KR100226368B1 (en) 1999-10-15
CA2040468A1 (en) 1991-10-18
GR3033236T3 (en) 2000-09-29
EP0643063A3 (de) 1995-10-11

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